Antibody fucosylation predicts disease severity in secondary dengue infection

Bournazos, Stylianos; Vo, Hoa Thi My; Duong, Veasna; Auerswald, Heidi; Ly, Sowath; Sakuntabhai, Anavaj; Dussart, Philippe; Cantaert, Tineke; Ravetch, Jeffrey V.

doi:10.1126/science.abc7303

Cited by 79 publications

(90 citation statements)

References 32 publications

(10 reference statements)

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“…Furthermore, post-translational modifications of IgG antibodies have been shown to significant impact their affinity for FcgR complexes and to correlate with dengue severity (41). Most notably, the presence of high levels of afucosylated IgG-a posttranslational modification which increases the affinity of the IgG Fc domain for FcgRIIIa (42)either before or after DENV infection has been associated with increased dengue severity (43)(44)(45). Finally, the presence of serum complementsuch as C1q and C3 -can inhibit IgG mediated ADE both in vitro and in vivo, ostensibly by interfering with the ability of IgG Fc to interact with FcgR and/or forcing a complement-bound antibody into a configuration that is not amenable to fusion and viral entry (46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

Monomeric IgA Antagonizes IgG-Mediated Enhancement of DENV Infection

et al. 2021

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Dengue virus (DENV) is a prevalent human pathogen, infecting approximately 400 million individuals per year and causing symptomatic disease in approximately 100 million. A distinct feature of dengue is the increased risk for severe disease in some individuals with preexisting DENV-specific immunity. One proposed mechanism for this phenomenon is antibody-dependent enhancement (ADE), in which poorly-neutralizing IgG antibodies from a prior infection opsonize DENV to increase infection of Fc gamma receptor-bearing cells. While IgM and IgG are the most commonly studied DENV-reactive antibody isotypes, our group and others have described the induction of DENV-specific serum IgA responses during dengue. We hypothesized that monomeric IgA would be able to neutralize DENV without the possibility of ADE. To test this, we synthesized IgG and IgA versions of two different DENV-reactive monoclonal antibodies. We demonstrate that isotype-switching does not affect the antigen binding and neutralization properties of the two mAbs. We show that DENV-reactive IgG, but not IgA, mediates ADE in Fc gamma receptor-positive K562 cells. Furthermore, we show that IgA potently antagonizes the ADE activity of IgG. These results suggest that levels of DENV-reactive IgA induced by DENV infection might regulate the overall IgG mediated ADE activity of DENV-immune plasma in vivo, and may serve as a predictor of disease risk.

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Section: Discussionmentioning

confidence: 99%

Monomeric IgA Antagonizes IgG-Mediated Enhancement of DENV Infection

et al. 2021

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“…The well-known dengue ADE has been associated with poorly neutralizing cross-reactive antibodies against a heterologous viral serotype, leading to increased infection of FcγR-expressing cells 58 . Recent findings suggested that an increase in afucosylated antibodies contribute to dengue ADE 59 . In contrast, vaccine-associated enhanced respiratory disease induced by respiratory syncytial virus has not been found to be antibody-dependent 60 .…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 hijacks neutralizing dimeric IgA for enhanced nasal infection and injury

Zhou

Chan

et al. 2021

Preprint

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Robust severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in nasal turbinate (NT) accounts for high viral transmissibility, yet whether neutralizing IgA antibodies can control it remains unknown. Here, we evaluated receptor binding domain (RBD)-specific monomeric B8-mIgA1 and B8-mIgA2, and dimeric B8-dIgA1 and B8-dIgA2 against intranasal SARS-CoV-2 challenge in Syrian hamsters. These antibodies exhibited comparably potent neutralization against authentic virus by competing with human angiotensin converting enzyme-2 (ACE2) receptor for RBD binding. While reducing viruses in lungs, pre-exposure intranasal B8-dIgA1 or B8-dIgA2 led to 81-fold more infectious viruses and severer damage in NT than placebo. Virus-bound B8-dIgA1 and B8-dIgA2 could engage CD209 as an alternative receptor for entry into ACE2-negative cells and allowed viral cell-to-cell transmission. Cryo-EM revealed B8 as a class II neutralizing antibody binding trimeric RBDs in 3-up or 2-up/1-down conformation. Therefore, RBD-specific neutralizing dIgA engages an unexpected action for enhanced SARS-CoV-2 nasal infection and injury in Syrian hamsters.

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“…For example, afucosylation of the HIV broadly neutralizing monoclonal antibody b12 did not enhance pre-exposure protection against a mucosal challenge in a rhesus macaque model, despite in vitro enhancement of ADCC activity, 95 yet postexposure therapeutic efficacy against an intraperitoneal challenge was enhanced via increased ADCC/ADCP accompanied by lower viral loads for a highly potent broadly neutralizing HIV antibody, 3BNC117, in a humanized mouse model. 94 Importantly, given recent associations between afucosylated antibodies and disease severity in the context of Dengue virus and SARS-CoV-2, 70,[96][97][98] reducing interaction with FcγR3A may be critical to avoid monoclonal antibody-mediated immunopathology for some viral infections.…”

Section: Lesson 1: Enhancing Effector Function Through the Fc Can Increase Therapeutic Antibody Potency And Efficacymentioning

confidence: 99%

Building a better antibody through the Fc: advances and challenges in harnessing antibody Fc effector functions for antiviral protection

Gunn

Bai

2021

Human Vaccines & Immunotherapeutics

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Antibodies can provide antiviral protection through neutralization and recruitment of innate effector functions through the Fc domain. While neutralization has long been appreciated for its role in antibodymediated protection, a growing body of work indicates that the antibody Fc domain also significantly contributes to antiviral protection. Recruitment of innate immune cells such as natural killer cells, neutrophils, monocytes, macrophages, dendritic cells and the complement system by antibodies can lead to direct restriction of viral infection as well as promoting long-term antiviral immunity. Monoclonal antibody therapeutics against viruses are increasingly incorporating Fc-enhancing features to take advantage of the Fc domain, uncovering a surprising breadth of mechanisms through which antibodies can control viral infection. Here, we review the recent advances in our understanding of antibody-mediated innate immune effector functions in protection from viral infection and review the current approaches and challenges to effectively leverage innate immune cells via antibodies.

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Antibody fucosylation predicts disease severity in secondary dengue infection

Cited by 79 publications

References 32 publications

Monomeric IgA Antagonizes IgG-Mediated Enhancement of DENV Infection

Monomeric IgA Antagonizes IgG-Mediated Enhancement of DENV Infection

SARS-CoV-2 hijacks neutralizing dimeric IgA for enhanced nasal infection and injury

Building a better antibody through the Fc: advances and challenges in harnessing antibody Fc effector functions for antiviral protection

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